本文選題：手性分離 + 苯磺酸氨氯地平��； 參考：《湘潭大學(xué)》2017年博士論文

【摘要】：使用純對(duì)映異構(gòu)體作為新藥原料是近年來(lái)制藥領(lǐng)域的一個(gè)重要趨勢(shì)。目前在臨床上使用的藥物一半以上具有手性結(jié)構(gòu),且銷售領(lǐng)先的藥物品種中,多數(shù)藥物是存在手性活性的。目前對(duì)手性藥物的分離多為實(shí)驗(yàn)室規(guī)模的微量分離分析,而能用于放大并進(jìn)行較大規(guī)模甚至工業(yè)化生產(chǎn)的外消旋拆分方法難以建立。本論文對(duì)一種手性降壓藥苯磺酸氨氯地平進(jìn)行手性分離研究,采用表面印跡技術(shù)和膜技術(shù),制備了幾種不同的表面印跡復(fù)合材料,展現(xiàn)出對(duì)苯磺酸氨氯地平一定的分離能力。實(shí)驗(yàn)中所采用的方法適于進(jìn)一步放大,有望為該藥物大規(guī)模化手性分離提供潛在的技術(shù)參考。具體研究工作如下:1.以聚偏氟乙烯中空纖維膜為支撐載體制備了分子印跡中空纖維復(fù)合膜,結(jié)合自制的膜組件,對(duì)苯磺酸氨氯地平進(jìn)行錯(cuò)流萃取分離。優(yōu)化了各種錯(cuò)流萃取實(shí)驗(yàn)條件,通過(guò)D-酒石酸和磺丁基醚-β-環(huán)糊精雙手性添加劑的使用,在最佳條件下,錯(cuò)流萃取分離系統(tǒng)的最佳對(duì)映異構(gòu)體過(guò)量值達(dá)到了17.84%。實(shí)驗(yàn)發(fā)現(xiàn),基于分子印跡孔穴的選擇性滲透和雙手性添加劑分別對(duì)兩種不同對(duì)映異構(gòu)體的優(yōu)先俘獲作用構(gòu)成了三重識(shí)別機(jī)制,并很好地解釋了該錯(cuò)流分離系統(tǒng)的手性選擇性。該方法結(jié)合了膜分離的易于擴(kuò)大生產(chǎn)和分子印跡膜的選擇性和穩(wěn)定性,可連續(xù)操作,有望為氨氯地平的工業(yè)化手性分離提供一定的理論參考。2.以介孔二氧化硅微球?yàn)檩d體,采用表面印跡技術(shù),通過(guò)沉淀聚合法,分別以甲基丙烯酸及乙二醇二甲基丙烯酸為單體和交聯(lián)劑,制備了對(duì)S-苯磺酸氨氯地平特異性識(shí)別的高性能表面印跡介孔微球。通過(guò)熱重分析和透射電鏡表征,發(fā)現(xiàn)制備的表面印跡微球具有較薄的印跡層,約為45 nm。制備的表面印跡微球具有快速的吸附動(dòng)力學(xué)和較大的吸附能力,在20 min內(nèi)達(dá)到飽和吸附,最大吸附量為245 mg/g。這證明制備的印跡材料表面存在大量的識(shí)別位點(diǎn),有利于模板分子與分子印跡材料再結(jié)合,減小了吸附過(guò)程的傳質(zhì)阻力。將印跡材料制備成分離柱(3.0 cm柱長(zhǎng)),對(duì)苯磺酸氨氯地平進(jìn)行動(dòng)態(tài)分離,獲得了對(duì)映異構(gòu)體過(guò)量值為11.3%的分離效果。該方法操作簡(jiǎn)便,易于工業(yè)放大。3.對(duì)介孔二氧化硅微球進(jìn)行雙鍵化和羧基化改性,制備成羧基化硅球。將模板分子S-苯磺酸氨氯地平提前固定在羧基化硅球上,采用表面印跡技術(shù),通過(guò)用乙二醇二縮水甘油醚對(duì)硅球表面羧基進(jìn)行水解縮合反應(yīng),制備了高性能的表面印跡微球。對(duì)比了羧基化硅球和表面印跡微球的吸附動(dòng)力學(xué)和吸附性能,發(fā)現(xiàn)表面印跡微球在20 min內(nèi)達(dá)到飽和吸附,最大吸附能力為137 mg/g,均比羧基化硅球吸附能力略低。這是因?yàn)楸砻骠然饪s合反應(yīng)后,印跡材料表面的功能基團(tuán)減少。將印跡材料制備成分離柱(2.3 cm柱長(zhǎng)),對(duì)苯磺酸氨氯地平進(jìn)行動(dòng)態(tài)分離,發(fā)現(xiàn)最佳羧基改性條件下制備的分離柱獲得了對(duì)映異構(gòu)體過(guò)量值為13.8%的分離效果。通過(guò)采用該模板固定法,提高了分子印跡程序中的模板利用率,從而進(jìn)一步提高了表面分子印跡效率。4.以介孔二氧化硅微球?yàn)檩d體,采用表面印跡技術(shù),通過(guò)沉淀聚合法,分別以N-異丙基丙烯酰胺及N,N-亞甲基雙丙烯酰胺為單體和交聯(lián)劑,制備了溫敏型的對(duì)S-苯磺酸氨氯地平特異性識(shí)別的表面印跡微球。透射電鏡表征發(fā)現(xiàn)表面印跡微球具有較薄的印跡層,約為16 nm。制備的表面印跡微球具有非�？焖俚奈絼�(dòng)力學(xué)和非常大的吸附能力,在5 min內(nèi)達(dá)到飽和吸附,最大吸附量達(dá)到441mg/g。這證明制備的印跡材料極薄的表面印跡層存在大量的識(shí)別位點(diǎn),更利于模板分子與表面印跡材料再結(jié)合,減小了吸附過(guò)程的傳質(zhì)阻力。發(fā)現(xiàn)該材料在質(zhì)子性溶劑中吸附能力降低,但印跡材料表現(xiàn)出對(duì)溫度的敏感性,在35℃時(shí)獲得了最佳吸附效果;材料的溫敏特性可用于控制目標(biāo)分子洗脫。將印跡材料對(duì)苯磺酸氨氯地平進(jìn)行柱分離,獲得了對(duì)映異構(gòu)體過(guò)量值為10.2%的分離效果。5.以stober二氧化硅微球?yàn)檩d體,采用表面印跡技術(shù),通過(guò)溶膠-凝膠聚合法,分別以3-氨丙基三乙氧基硅烷及硅酸四乙酯為單體和交聯(lián)劑,制備了S-苯磺酸氨氯地平的表面印跡微球。制備的表面印跡微球在60 min內(nèi)達(dá)到飽和吸附,最大吸附能力約為94 mg/g,印跡因子為1.52。通過(guò)測(cè)定材料的重復(fù)使用性能,材料能在使用7個(gè)吸附-釋放周期后基本維持其吸附性能,證明以硅材料制備的印跡層穩(wěn)定性好,滿足多次重復(fù)使用的要求。將印跡材料制備成分離柱,獲得對(duì)苯磺酸氨氯地平一定的動(dòng)態(tài)分離效果。該方法在室溫下容易制備、不受熱力學(xué)或化學(xué)分解的影響、應(yīng)用環(huán)境友好的反應(yīng)溶劑(常用水或乙醇),成本低廉。
[Abstract]:The use of pure enantiomers as new drug materials is an important trend in the pharmaceutical field in recent years. At present, more than half of the drugs used in clinical use are chiral structures, and most drugs are chiral in the leading drug varieties. In this paper, the chiral separation method of amlodipine, a chiral hypotensive drug, was studied in this paper. Several different surface imprinting materials were prepared by surface imprinting technology and membrane technology. The method used in the experiment is suitable for further enlargement, and it is expected to provide potential technical reference for the large-scale chiral separation of the drug. The specific research work is as follows: 1. the molecularly imprinted hollow fiber composite membrane was prepared with polyvinylidene fluoride hollow fiber membrane as the support carrier, and the homemade membrane module was combined with the amhilylidene sulfonic acid. The experimental conditions of different flow extraction were optimized. Through the use of D- tartaric acid and sulfonyl ether - beta cyclodextrin double hand additive, the best enantiomer overvalue of the staggered extraction separation system reached the 17.84%. experiment under the best conditions. The selective infiltration and hands based on the molecular imprinting hole were found. The sex additive constitutes a three recognition mechanism for the first capture of two different enantiomers, and the chiral selectivity of the system is well explained. This method combines the selectivity and stability of the membrane separation and the selectivity and stability of the molecularly imprinted membrane. It can be operated continuously and is expected to be the industrialization of amlodipine. Chiral separation provides a theoretical reference.2. with mesoporous silica microspheres as the carrier. The high performance surface imprinted mesoporous microspheres for the specific identification of amlodipine S- benzensulfonic acid are prepared by surface imprinting technology and by precipitation polymerization, respectively, with methacrylic acid and ethylene glycol two methacrylic acid as monomers and crosslinker. The surface imprinted microspheres prepared by the reanalysis and transmission electron microscopy show that the imprinted microspheres have a thin imprinting layer. The surface imprinted microspheres prepared by 45 nm. have a rapid adsorption kinetics and a larger adsorption capacity. The surface of the imprinted microspheres is saturated in 20 min and the maximum adsorption amount is 245 mg/g.. The surface of the imprinted material has a large number of identification. The site, which is beneficial to the combination of template molecules and molecularly imprinted materials, reduces the mass transfer resistance in the adsorption process. The imprinted material is prepared from the column (3 cm column long), and the amlodipine sulfonic acid is separated dynamically. The separation effect of the overdose of enantiomers is 11.3%. This method is easy to operate and is easy to be amplified by industrial.3. to mediate Kong Er. The silicon oxide spheres were prepared by double bonding and carboxylation. The template molecule S- amlodipine was immobilized on the carboxylic silicon ball in advance. The surface imprinting technique was used to prepare a high performance surface imprinted microsphere by using ethylene glycol two glycidyl ether to hydrolyze the carboxyl group on the surface of silicon ball. The adsorption kinetics and adsorption properties of carboxyl silicon spheres and surface imprinted microspheres were found. It was found that the surface imprinted microspheres reached saturation adsorption in 20 min and the maximum adsorption capacity was 137 mg/g, which were slightly lower than that of carboxyl silicon spheres. This was due to the reduction of functional groups on the surface of trace materials after the hydrolysis and condensation reaction of the surface carboxyl group. The separation of amlodipine benzenate from the column (2.3 cm column length) was carried out. It was found that the separation column prepared under the optimum carboxyl modified conditions obtained the separation effect of 13.8% of the overdose of enantiomers. By using the template fixing method, the template utilization rate in the molecular imprinting program was improved and the surface fraction was further improved. .4. with mesoporous silica microspheres was used as the carrier. Surface imprinting technology was used to prepare the surface imprinted microspheres for the specific identification of amlodipine S- benzoate with N- isopropyl acrylamide and N, N- methylene diacrylamide respectively by precipitation polymerization. The surface imprinted microspheres for the specific identification of amlodipine by Wen Min type were prepared. The surface imprinted microspheres have a thin imprinting layer. The surface imprinted microspheres, about 16 nm., have very fast adsorption kinetics and very large adsorption capacity. The saturated adsorption is reached within 5 min, and the maximum adsorption capacity reaches 441mg/g.. It is proved that the extremely thin surface imprinting layer of the imprinted material has a large number of identification sites, which is more conducive to the template. It is found that the adsorptive capacity of the material is reduced by the combination of the surface imprinted material and the surface imprinting material. It is found that the adsorptive capacity of the material is reduced in the proton solvent, but the imprinted material shows the sensitivity to the temperature, and the best adsorption effect is obtained at 35 C. The temperature sensitive property of the material can be used to control the elution of the target molecules. The separation effect of chlordipine column was obtained. The separation effect of the overdose of enantiomers was 10.2%.5. with Stober silica microspheres as the carrier. The surface printing of amlodipine S- benzenic sulfonic acid was prepared by the surface imprinting technique and the sol-gel polymerization, with 3- amipropyl triethyl silane and four ethyl silicate as monomers and crosslinking agents, respectively. The surface imprinted microspheres reached saturation adsorption in 60 min, the maximum adsorption capacity was about 94 mg/g, and the imprinting factor was 1.52. by measuring the reusable properties of the material. The material could basically maintain its adsorption properties after using 7 adsorption release cycles. It was proved that the imprinting layer prepared by silicon material was stable and satisfied multiple repetitions. The dynamic separation effect of amlodipine benzoate was obtained by preparing the imprinted material from the column. This method is easy to be prepared at room temperature without the influence of thermodynamics or chemical decomposition. The application of environmentally friendly reaction solvent (commonly used water or ethanol) is low cost.
【學(xué)位授予單位】：湘潭大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：TQ460.1;O631

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 張亨;中空纖維膜研究進(jìn)展[J];化工新型材料;2003年04期

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本文編號(hào)：2034486